Journal
CANCER IMMUNOLOGY RESEARCH
Volume 5, Issue 12, Pages 1152-1161Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-17-0189
Keywords
-
Categories
Funding
- NCI Cancer Center [2-P30-CA-016520-35]
- Breast Cancer Alliance Research Foundation
- Breast Cancer Immunotherapy Funds
- Breast Cancer Research Foundation
- Pennsylvania Department of Health [0972501]
- University of Pennsylvania
- Center for Cellular Immunotherapies
- Tumor Tissue and Biospecimen Bank (TTAB) of the Abramson Cancer Center
- FHCRC/UW Cancer Consortium Cancer Center Support Grant of the NIH [P30 CA015704]
- [NCI5R01CA120409]
Ask authors/readers for more resources
Chimeric antigen receptors (CAR) are synthetic molecules that provide new specificities to T cells. Although successful in treatment of hematologic malignancies, CAR T cells are ineffective for solid tumors to date. We found that the cell-surface molecule c-Met was expressed in similar to 50% of breast tumors, prompting the construction of a CAR T cell specific for c-Met, which halted tumor growth in immune-incompetent mice with tumor xenografts. We then evaluated the safety and feasibility of treating metastatic breast cancer with intratumoral administration of mRNA-transfected c-Met-CAR T cells in a phase 0 clinical trial (NCT01837602). Introducing the CAR construct via mRNA ensured safety by limiting the nontumor cell effects (on-target/off-tumor) of targeting c-Met. Patients with metastatic breast cancer with accessible cutaneous or lymph node metastases received a single intratumoral injection of 3 x 10(7) or 3 x 10(8) cells. CAR T mRNA was detectable in peripheral blood and in the injected tumor tissues after intratumoral injection in 2 and 4 patients, respectively. mRNA c-Met-CAR T cell injections were well tolerated, as none of the patients had study drug-related adverse effects greater than grade 1. Tumors treated with intratumoral injected mRNA c-Met-CAR T cells were excised and analyzed by immunohistochemistry, revealing extensive tumor necrosis at the injection site, cellular debris, loss of c-Met immunoreactivity, all surrounded by macrophages at the leading edges and within necrotic zones. We conclude that intratumoral injections of mRNA c-Met-CAR T cells are well tolerated and evoke an inflammatory response within tumors. (C) 2017 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available